The present invention relates to the use of at least one activator of receptors of PPAR-xcex3 type for preparing a pharmaceutical composition, the composition being intended for treating skin disorders related to an abnormality of the differentiation of epidermal cells.
Many skin disorders exist which are related to an abnormality of the differentiation of epidermal cells; as examples mention may be made of psoriasis, eczema, dermatitides, common acne, keratoses, including ichthyosis, and skin cancers. This abnormality of the differentiation of epidermal cells is generally accompanied by a hyperproliferation of epidermal cells. To treat these disorders, various pharmaceutical approaches have been envisaged. However, no treatment at this time is entirely satisfactory. Thus there is a need to improve the existing treatments.
Peroxisomes are small organelles which are closely related to mitochondria and which contain a series of enzymes which are characteristic of the metabolism of hydrogen peroxide (catalase, urate oxidase, D-amino acid oxidase), and fatty acid xcex2-oxidation enzymes. Peroxisome proliferators are principally groups of chemical products which comprise hypolipidaemiants such as clofibrate, herbicides and industrial plastics such as phthalate esters. These peroxisome proliferators are non-genotoxic carcinogens which activate receptors, which are termed PPARs, and which are part of the steroid nuclear receptor super-family. These receptors can be activated by peroxisome proliferators, they can also be activated by natural fatty acids, and they thus stimulate the expression of genes which encode enzymes involved in peroxisomal and mitochondrial xcex2-oxidation, or alternatively which encode P450-4A6 fatty acid xcex2-hydroxylase.
The set of references suggests a role for PPARs in the regulation of metabolism and the homeostasis of lipids.
PPAR receptors activate transcription by binding to DNA sequence elements, which are termed peroxisome proliferator response elements (PPRE), in the form of a heterodimer with retinoid X receptors (termed RXRs).
Three subtypes of human PPAR have been identified and described: PPARxcex1, PPARxcex3 and PPARxcex4 (or NUC1).
In patent application WO 96/33724, it has been described that compounds which are selective for the PPARxcex3s, such as a prostaglandin J2 or D2, are potential active agents for treating obesity and diabetes.
Moreover, in patent application WO 95/35108, it has been described that thiazolidinediones, more particularly ciglitazone, have an activity in the treatment of psoriasis by inhibiting the proliferation of keratinocytes.
The Applicant has just discovered that when the differentiation of human keratinocytes is induced with a high calcium concentration, the level of expression of the PPARs, more particularly of PPARxcex3, is increased. Also, the Applicant has observed that the level of expression of the PPARs, more particularly of PPARxcex3, in psoriatic lesioned skin is noticeably reduced with respect to that in non-lesioned skin.
Thus, a subject of the present invention is the use of at least one activator of receptors of PPAR-xcex3 type for preparing a pharmaceutical composition, the composition being intended for treating skin disorders related to an abnormality of the differentiation of epidermal cells.
The pharmaceutical composition is preferably a dermatological composition.
xe2x80x9cActivator of receptors of PPAR-xcex3 typexe2x80x9d is intended to mean, according to the invention, any compound which, in a transactivation test as described in Kliewer et al., Nature 358, 771-774, 1992, has an AC50 relative to PPAR-xcex3 which is lower than or equal to 1 xcexcM.
Preferably, the activator of receptors of PPAR-xcex3 type has an AC50 relative to PPAR-xcex3 which is lower than or equal to 200 nM, and advantageously which is lower than or equal to 50 nM.
Preferably, the activator of receptors of PPAR-xcex3 type is specific, i.e. it has a ratio R1 of AC50 relative to PPAR-xcex3 over AC50 relative to PPARxcex1 which is lower than or equal to 10xe2x88x921. Preferably, R1 is lower than or equal to 0.05, and more advantageously is lower than or equal to 0.02.
The AC50 is the concentration of xe2x80x9cactivatorxe2x80x9d compound required to give 50% of an enzymatic activity (luciferase) which is a reporter of the activation due to the compound via one of the PPAR receptors, and more particularly of PPAR-xcex1 or PPAR-xcex3 type.
The compounds more particularly used in the present invention are:
5-{4-[2-(methylpyrid-2-yl-amino)ethoxy]benzyl-thiazolidine-2,4-dione;
3-{4-[2-(benzoxazol-2-ylmethylamino)ethoxy]phenyl}-2-ethoxypropionic acid;
(+)-3-{4-[2-(benzoxazol-2-ylmethylamino)ethoxy]phenyl}-2-ethoxypropionic acid;
(xe2x88x92)-3-{4-[2-(benzoxazol-2-ylmethylamino)ethoxy]phenyl}-2-ethoxypropionic acid;
15-deoxy-xcex9412,14-prostaglandin J2(15-d PGJ2).
It is all the more surprising that the compounds used in the present invention treat this type of skin disorder, since some of them have a weak, or even no inhibitory activity on the proliferation of keratinocytes, such as 5-{4-[2-(methylpyrid-2-yl-amino)ethoxy]benzyl}thiazolidine-2,4-dione and 15-d PGJ2.
Preferably, the activator of receptors of PPAR-xcex3 type used has a percentage of inhibition of keratinocyte proliferation which is less than or equal to 20% when it is used at a concentration which is lower than or equal to 100 nM (see example below).
The pharmaceutical composition according to the invention comprises a physiologically acceptable medium.
Other characteristics, aspects, subjects and advantages of the invention will emerge even more apparent upon reading the description which will follow, as well as the various concrete, but in no way limiting examples which are intended to illustrate it.
Among the disorders related to an abnormality of the differentiation of epidermal cells, more particularly keratinocytes, mention may be made more particularly of psoriasis, eczema, lichen planus, skin lesions associated with lupus, dermatitides such as atopic, seborrho or solar dermatitis, keratoses such as seborrhoeic keratosis, senile, actinic, light-induced or follicular keratosis, common acne, keloids, nevi, warts, ichthyoses and skin cancers.
Among the disorders related to an abnormality of the differentiation of epidermal cells, abnormalities of the barrier function, such as atopic dermatitis, eczema and psoriasis are preferably mentioned.
Administration of the composition according to the invention can be carried out via the enteral, parenteral or topical route. Preferably, the pharmaceutical composition is packaged in a form which is suitable for application via the topical route.
Via the enteral route, the composition, more particularly the pharmaceutical composition, can be in the form of tablets, gelatin capsules, dragees, syrups, suspensions, solutions, powders, granules, emulsions, microspheres or nanospheres or lipidic or polymeric vesicles which enable controlled release. Via the parenteral route, the composition can be in the form of solutions or suspensions for perfusion or for injection.
The compounds are used according to the invention are generally administered at a daily dose of about 0.001 mg/kg to 100 mg/kg of body weight, taken in 1 to 3 dosage intakes.
Via the topical route, the pharmaceutical composition according to the invention is more particularly intended for treatment of the skin and of the mucous membranes, and can be in the form of pasty ointments, creams, milks, creamy ointments, powders, impregnated pads, solutions, gels, sprays, lotions or suspensions. It can also be in the form of microspheres or nanospheres or lipidic or polymeric vesicles or polymeric patches and hydrogels which enable controlled release. This topical-route composition can be either in anhydrous form or in aqueous form.
The compounds are used via the topical route at a concentration generally between 0.001% and 10% by weight, preferably between 0.01 and 1% by weight, relative to the total weight of the composition.
The compositions as described above can of course also contain inert or even pharmacodynamically active additives or combinations of these additives, and in particular: wetting agents; depigmenting agents such as hydroquinone, azelaic acid, caffeic acid or kojic acid; emollients; hydrating agents such as glycerol, PEG-400, thiamorpholinone and derivatives thereof, or alternatively urea; anti-seborrhoeic agents or anti-acne agents such as S-carboxymethylcysteine and S-benzylcystamine and the salts or derivatives thereof, or benzoyl peroxide; antifungal agents such as ketoconazole or poly-4,5-methylene-3-isothiazolidones; antibacterial agents, carotenoids and in particular xcex2-carotene; anti-psoriatic agents such as anthralin and derivatives thereof; eicosa-5,8,11,14-tetraynoic acid and eicosa-5,8,11-triynoic acid, the esters and amides thereof and finally retinoids.
These compositions can also contain flavour-enhancing agents, preserving agents such as para-hydroxybenzoic acid esters, stabilizers, moisture regulators, pH regulators, osmotic pressure modifiers, emulsifying agents, UV-A and UV-B screening agents, and antioxidants such as xcex1-tocopherol, butylhydroxyanisole or butylhydroxytoluene.
Of course, persons skilled in the art will take care to choose the optional compound(s) to be added to these composition in such a way that the advantageous properties which are intrinsically attached to the present invention are not, or are not substantially, altered by the addition envisaged.
Several examples will now be given, which are intended to illustrate the present invention, and which are in no way limiting.